Risk of venous thromboembolism in patients with rheumatoid arthritis: a meta-analysis of observational studies

Background Thrombotic events, such as venous thromboembolism (VTE) are a major health complication linked to rheumatoid arthritis (RA). We performed a meta-analysis to evaluate the risk of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in adults with RA compared to the general population. Methods MEDLINE and EMBASE databases were searched from inception to April 2022 to identify publications meeting the following criteria: (1) prospective and retrospective original data from cohort or case-control studies; (2) pre-specified RA definition; (3) clearly defined VTE outcomes; (4) reported risk estimate and 95% confidence intervals (95% CIs); (5) at least sex- and age-matched to comparison group; and (6) English language. Of 372 studies screened, 14 were included (602,760 RA patients, 123,076 VTE events) and their quality was assessed by an adaptation of the STROBE quality scoring scale. Results The pooled risk ratios of VTE, DVT and PE in patients with RA were 1.57 (95% CI 1.41–1.76), 1.58 (95% CI 1.26–1.97) and 1.57 (95% CI 1.30–1.88), respectively. The I2 value of 92%, 94% and 92% for VTE, DVT and PE analyses, suggesting considerable heterogeneity. There were no significant differences in risk estimates among the five subgroup analyses: quality score (P = 0.35, I2 = 0%); sex (P = 0.31, I2 = 1.7%); study year (P = 0.81, I2 = 0%); population source (P = 0.35, I2 = 0%); study design (P = 0.62, I2 = 0%). Conclusions Results show that patients with RA are at a higher risk of VTE, DVT and PE compared to the general population. Supplementary Information The online version contains supplementary material available at 10.1186/s41927-024-00376-9.


Information sources
6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies.
Specify the date when each source was last searched or consulted.

5
Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.

Supplementary material
Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

6-7
Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

7
Data items 10a List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

10b
List and define all other variables for which data were sought (e.g.participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information.

6
Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

7
Effect measures 12 Specify for each outcome the effect measure(s) (e.g.risk ratio, mean difference) used in the synthesis or presentation of results.6 Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g.tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

6-7
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

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13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.8 13d Describe any methods used to synthesize results and provide a rationale for the choice(s).If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

8
13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g.subgroup analysis, meta-regression).8 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.8 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).8 Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.None

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

8-9
16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

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Study characteristics 17 Cite each included study and present its characteristics.9 and Table 1 Risk of bias in studies 18 Present assessments of risk of bias for each included study.9 and Table 1 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.
Table 2 Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.14-15 and Table 1 20b Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.

Table 1 .
Quality scoring scale for cohort and case-control studies is a non-selected sample (random sample, population-based (databases that include all cases) Clinical: usually patients seen in one or several clinics, hospitals (selected samples that do not represent everyone) Inception cohort: all cases seen at the disease onset or within the same time period (i.e.within the first year of disease) and then follow them (usually incident cases) Statistics under the fixed effects model and the random effects model for venous thromboembolism outcome, n=11 studies 14-1520c Present results of all investigations of possible causes of heterogeneity among study results.1520dPresentresults of all sensitivity analyses conducted to assess the robustness of the synthesized results.15Reportingbiases21Presentassessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.27Reportwhich of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.NoneFrom: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ 2021;372:n71.doi:10.1136/bmj.n71Formore information, visit: http://www.prisma-statement.org/Additional File 3:

Table 2 .
Heterogeneity statistics for venous thromboembolism outcome, n=11 studies

Table 3 .
Asymptomatic heterogeneity tests for venous thromboembolism outcome, n=11 studies

Table 4 .
Bootstrap tests for venous thromboembolism outcome, n=11 studies 95% confidence interval VTE: venous thromboembolism Johannesdottir et al. (2012) was excluded from the study design from the subgroup analysis, as it is a case-control study